The clinical condition of gingival overgrowth consists of excess gingival tissues that creates disturbances in the oral environment and creates related systemic complications. Drug-induced gingival overgrowth occurs as a side effect of certain medications. Previous studies from our laboratory have shown that phenytoin induced gingival overgrowth lesions are more fibrotic, less cellular, and contain elevated levels of connective tissue growth factor (CTGF) than lesions formed from the pharmacological action of cyclosporine-A or nifedine. This finding is significant since CTGF is capable of stimulating the accumulation of insoluble collagen in cultured human gingival fibroblasts. Additionally, CTGF levels are elevated in other fibrotic conditions including, but not limited to, scleroderma, atherosclerosis, and kidney failure. The regulation and downstream consequences of increased CTGF expression currently are not well understood. Preliminary data indicate that prostaglandin E2 (PGE2) is capable of up-regulating CTFG expression in gingival fibroblasts and this effect is tissue-specific. The goals of the current proposal are (1) to determine the intracellular pathways through which PGE2 regulates CTGF expression in primary human gingival fibroblasts, (2) compare this response with other tissue-derived fibroblasts including human primary dermal fibroblasts, primary human renal mesangial cells, and control human fetal lung (IMR9O) fibroblasts, (3) determine the molecular mechanism underlying overgrowth and scleroderma by comparison with normal gingival and dermal fibroblasts, and (4) determine the target genes regulated by CTGF, specifically those involved with the normally tightly coupled processes of extracellular matrix degradation and biosynthesis. We hypothesize that tissue-specific differences exist in the regulation of CTGF expression. By defining the tissue-specific pathways by which PGE2 regulates CTGF expression we will provide a foundation by which therapeutic strategies targeted against specific fibrotic pathologies may be formulated.